CH656128A5 - OPTICALLY ACTIVE AND RACEMIC 1-ALKYL-1,2,3,4,6,7,12,12B-OCTAHYDROINDOLO (2,3-A) CHINOLIZINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The present invention relates to new, optically active or racemic trans- and / or cis-l- [2 '- (alkoxycarbo-65 nyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2, 3,4,6,7,12,12b-octahy-droindolo [2,3-a] quinolizines, processes for their preparation and medicaments containing these compounds; the drugs are particularly effective against circulatory diseases.

656 128

10th

It is known that the racemic cis-apovincamic acid esters of the general formula

(I)

(IIb)

O X - OH

and optically active cis-apovincamic acid esters of the general formula 15

(Ile)

and or

(Ic)

wherein

R, and R2 are identical or different and represent alkyl radicals having 1 to 6 carbon atoms,

have valuable pharmacological effects, of which the (-t -) - cis-apovincamic acid ethyl ester is particularly distinguished by its significant vasodilatory effect.

The racemic cis-apovincamic acid esters of the general formula I and the optically active cis-apovincamic acid esters of the general formula Ic are prepared in accordance with the Hungarian patent specification 163 143 in such a way that the vinamine, which also has valuable therapeutic effects, hydrolyzes, then the vincamic acid obtained in the desired ester is transferred and the corresponding apovincamic acid ester is obtained from the vincamic acid ester by elimination of water, or apovincamine is previously prepared from the vincamine by elimination of water, then this is hydrolyzed and the apovincamic acid obtained is converted into the corresponding ester. However, these processes have the disadvantage that vincamine must first be prepared in a multistage synthesis, whereupon the corresponding apovincamic acid ester can be prepared from it in a yield of only at most "60%.

The racemic trans-apovincamic acid esters of the general formula I are described in the published European patent application 13 315.

The object of the invention is to provide novel 1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines which have superior pharmacological effects, a superior process for the preparation thereof and these To create compounds containing compounds.

The invention relates to optically active trans and /

or cis-1 - [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a ] quinolizines of the general formulas

(Hd)

X - OH

30 or racemic trans- and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7,12, 12b-octahy-droindolo [2,3-a] quinolizines of the general formula

(II)

H - OH

wherein

Rj and R; are identical or different and represent alkyl radicals having 1 to 6 carbon atoms,

45 and their acid addition salts.

The alkyl radicals represented by Rj and R2 can be straight-chain or branched. Examples of them are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl radicals. The alkyl radicals for which R and R2 are preferably those having 1 to 4, in particular 1 or 2, carbon atoms. The ethyl radical is very particularly preferred as the alkyl radical which R 2 can stand for.

The invention also relates to processes for the preparation of the compounds according to the invention defined above. 55 The compounds of the formulas Ia, Ib, Ic and Id are obtained according to the invention by using racemic l- [2 '- (alkoxycarbonyl) ethyl-1,2,3,4,6,7-hexahydro-12H -indolo [2,3-a] quinolizin-5-ium derivatives of the general formula

(IIa)

2f - OK

(V)

11

656 128

wherein

R3 corresponds to the radical R, or is different therefrom and is alkyl having 1-6 carbon atoms and

X is an acid residue or an alkanolate residue with 1 to 6 carbon atoms,

with optically active dibenzoyl tartaric acid to optically active l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium derivatives of the general formulas and / or

and / or and / or r ^ N

(Va)

(Illb)

subjects them to optically active trans-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas

(Vb)

splits and this either

(a) with alkali metal hydrides to optically active trans-1 - [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo- [2,3- a] quinolizines of the general formulas

(Via)

(IVa)

(VIb)

esterified, wherein R4 corresponds to or is different from the radical R3 and means alkyl with 1-6 carbon atoms, and this with tert-alkyl nitrites with 4 to 8 carbon atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates, whereby compounds of Receives formulas IIa and IIb,

or by looking

(b) the compounds of the formulas Va and / or Vb listed above catalytically to give optically active cis-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6, 7,12,12b-octahydroindolo [2,3-a] quinolines of the general formulas

(IVb)

reduced, this an alkaline hydrolysis to optically active trans-1 - [2 '- (carboxy) ethyl] - 1-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo- [2,3 -a] quinolizines of the general formulas

(IVc)

and or

(Illa)

HO - 0 - C - 0

(IVd)

656 128

12

hydrogenated, this by alkaline hydrolysis in optically active cis-l- [2 '- (carboxy) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3- a] quinolizines of the general formulas

(IIIc),

and or

(HId)

converted this by esterification into optically active cis-1 - [2 '- (Alko- 25 xycarbonyl) ethyl] -l -alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2, 3-a] quinolizines of the general formulas

30th

(VIc)

and or

(VId).

transferred and finally treated with tert-alkyl nitrites having 4 to 8 carbon atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates, giving the compounds of the formulas Ile and / or Ild.

Another method relates to the preparation of the racemic trans and / or cis compounds of the formula II, starting from racemic compounds of the formula V. Racemic compounds of the formula V are reduced with alkali hydrides to racemic trans compounds of the formula IV and racemic compounds of the formula V are catalytically reduced to racemic cis compounds of the formula IV. The racemic trans and / or cis compounds of the formula IV are subjected to hydrolysis, giving racemic trans and / or cis compounds of the formula III. These are esterified to racemic trans and / or cis compounds of the formula VI and these are finally subjected to the nitroxation described above to give racemic trans and / or cis compounds of the formula II.

In a third process, compounds of the formulas IVa and / or IVb or IVc and / or IVd are used and carried out.

as described above, via the corresponding compounds of the formulas lilac and / or Illb or IIIc and / or Illd, which are then esterified to give the compounds of the formulas Via and / or VIb or VIc and / or VId and nitrosated into the desired compounds Transfer compounds of the formulas IIa and / or IIb or Ile and / or Ild.

A fourth method also relates to the preparation of the four optically active compounds IIa and / or IIb or Ile and / or Ild mentioned. Compounds of the formulas lilac and / or Illb or IIIc and / or Illd are used as a starting point and these are converted into the compounds of the formulas Via and / or VIb or VIc and / or VId by esterification and the desired compounds are obtained by nitrosation , optically active connections.

The fifth method also relates to the preparation of the optically active compounds of the formulas IIa and / or IIb or Ile and / or Ild, which, as described above, from the optically active compounds of the formulas Via and / or VIb or VIc and / or VId obtained by nitrosation.

The last method according to the invention also relates to the preparation of the optically active compounds of the formulas IIa and / or IIb or Ile and / or Ild. In this process, one starts from the optically active compounds of the formulas Va and / or Vb and, as described above, converts them by catalytic hydrogenation into compounds of the formulas IVc and / or IVd and these then become compounds of the formulas Ile directly and / or Ile nitrosated, or the compounds of the formulas Va and / or Vb are subjected to hydrogenation with alkali metal hydrides, the compounds of the formulas IVa and / or IVb are obtained, which are then directly nitrosated into the compounds of the formulas IIa and / or IIb be transferred.

If intermediate compounds are obtained as a racemate, this can be split into the corresponding optically active compounds.

The last process step in all of the processes described is preferably carried out in aprotic dipolar solvents and / or in the presence of an alkanol of the formula R 1 - OH, where transesterification can occur.

If the compound according to the invention is obtained as a racemate, this can of course be split into the corresponding optically active compounds.

Optically active trans- and / or cis-1- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7,12 obtained according to the invention 12b-octahydroindolo [2,3-a] quinolizines of the general formulas IIa and / or IIb and or Ile and or Ild or racemic trans- and / or ice 1- [2 '- (alkoxycarbonyl) -2' - (hydroxyiminoj-ethyl) ] -l -alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formula II can be transesterified by known methods and / or converted into acid addition salts with acids and / or can be obtained acid addition salts of the optically active ice and / or trans-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-1,2,3,4, 6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas IIa and / or IIb and / or Ile and / or Ild or racemic ice and / or trans-l- [2 '- (alkoxy -carbonyl) -2 '- (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octa-hydroindolo [2,3-a] quinolizines of the general formula II in the corresponding convert free bases or other salts and / or cleave the racemic trans- and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-l, 2,3 obtained , 4,6,7,12, 12b-octahydroindolo [2,3-a] quinolizines of the general formula II or of acid addition salts thereof in the corresponding optically active isomers.

As an acid residue for which X "in the l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7-hexahydro-12H-indolo [usable as starting materials in the process according to the invention" 2,3-a] quinolizine-5-ium derivatives of the general formulas Va, Vb or V can be those of inorganic or organic acids, advantageously a perhalate residue, in particular a perchlorate residue, examples of alkanolate residues for which X in

13

656128

these compounds may be the alkyl radicals given above as examples, in particular the methanolate radical.

Cleavage of the racemic eis and trans-1- [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3- a] quinoli-zin-5-ium derivatives of the general formula V and of the racemic ice and trans-1 - [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7, 12, 12b-octahydroindolo [2,3-a] quinolizines of the general formula IV in their optically active isomers can advantageously be carried out with respect to the reaction inert organic solvents or solvent mixtures. Examples of such are aliphatic or aromatic hydrocarbons, such as dichloromethane, optionally substituted by 1 or more halogen atoms, and alkanols having 1 to 6 carbon atoms, such as methanol or ethanol, and mixtures thereof.

To reduce the l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5- ium derivatives of the general formulas Va and Vb are used as alkali metal hydride sodium borohydride, but lithium aluminum hydride can also be used, for example. This reduction can advantageously be carried out in alkanols having 1 to 6 carbon atoms, such as methanol or ethanol, or mixtures of these.

In the catalytic hydrogenation of l- [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-iumde Derivatives of the general formulas Va or Vb are expediently used as the catalyst palladium on bone carbon, but this reaction can also be carried out in the presence of any other metal catalyst which is customary in catalytic hydrogenation and is optionally deposited on a support. This analytical hydrogenation can be carried out with respect to the reaction inert organic solvents or solvent mixtures. Examples of such solvents or solvent mixtures are aprotic dipolar solvents, advantageously dimethylformamide, or protonic solvents, such as alkanols with 1 to carbon atom (s), advantageously methanol or ethanol, and mixtures of such.

The alkaline hydrolysis of l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas IVa , IVb, IVc or IVd can be carried out in mixtures of inorganic bases, such as alkali metal hydroxides, for example sodium hydroxide, alkanols with 1 to 6 carbon atoms and water.

The esterification of the l- [2 '- (carboxy) ethyl] -l-alkyl-1,2,3,4,6,7,12, 12b-octahydroindolo [2,3-a] quinolizines of the general formulas purple, Illb, IIIc or Illd and III can be carried out according to procedures known per se.

The hydrolysis of 1 - [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahy-droindolo [2,3-a] quinolizines of the general formulas IVa, IVb, IVc and IVd and esterification of the l- [2 '- (carboxy) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo obtained [2,3-a] Quinolizines of the general formulas lilac, Illb, IIIc or Illd are usually used in the event that R4 is in the l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2 obtained , 3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas Via, VIb, VIc or VId an alkyl radical other than R3 in the l- [2 '- (alkoxycarbonyl) in question represents ethyl] -l-alkyl-l, 2,3,4,6,7, 12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas IVa, IVb, IVc and IVd, the introduction of this other Al-kylrestes, which is particularly advantageous when the l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7-hexahydro-12H-indolo [ 2,3-a] chi-nolizin-5-ium derivatives of the general formulas Vc, Vd or respectively se V or l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas IVa, IVb, IVc and IVd with the other alkyl radical for R3 are less accessible than with the alkyl radical used. At the same time, purer l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general

Formulas VI, Via, VIb and VIc can be obtained as the foregoing intermediates. This is the only purpose of the measures mentioned, in the event that R4 and R3 mean the same alkyl radical.

To convert the l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas Via, VIb, VIc or VId or the general formulas IVa, IVb, IVc or IVd into the 1- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3, 4,6,7,12,12b-octahydroindolo- [2,3-a] quinolizines of the general formulas IIa, IIb, Ile and Ild are preferably used as tert-alkyl nitrites with 4 to 6 carbon atoms. Particularly preferred tert-alkyl nitrites are tert-butyl nitrite and tert-pentyl nitrite, the use of the former being very particularly preferred. In this reaction, benzene, toluene and / or xylene, for example, are used as aromatic hydrocarbon solvents and, for example, potassium tert-butoxide, sodium tert-butoxide, potassium tert-pentylate or sodium tert-pentylate are used as tert-alkali metal alcoholates. Dimethylformamide and / or dimethylacetamide, for example, can be used as optionally added aprotic dipolar solvents. In the event that the alkyl radical for which R] stands, from the alkyl radical, R4 or R3 of the l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4 used for this reaction, 6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas Via, VIb, VIc or VId or of the general formulas IVa, IVb, IVc or IVd means different, the preferred use of Alkanols of the general formula R] OH the introduction of the desired esterifying alkyl radical and as a solvent or catalyst, while, in the event that the alkyl radicals for which Rt and R4 or R3 are the same, this alkanol only serves as a solvent or catalyst.

The optically active l- [2 '- (carboxy) ethyl] -l-alkyl-1,2,3,4,6, 7,12,12b-octahydroindolo [2,3-a] serving as intermediates in the processes according to the invention Quinolizines of the general formulas lilac, Illb, IIIc and Illd have antihypoxic and antispasmodic effects and the optically active 1 - [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2, which also serves as intermediates in the process according to the invention, 3,4,6,7,12,12b-octahy-droindolo [2,3-a] quinolizines of the general formulas IVa, IVb, IVc or IVd or Via, VIb, VIc or VId have anti-allergic effects, an anti-bradykinin effect, Effects on the central nervous system, antiarrhythmic, antihypoxic, anticonvulsant, antidepressant, sedative, hypnotic and cholesterol and lipoprotein-lowering effects as well as effects against ulcers. These compounds are described in Hungarian patent specification 171 660, some of which also have a valuable vasodilatory effect.

In addition, all intermediate products of the process according to the invention are valuable starting materials for the production of other therapeutically active compounds with an indolequinolizine or eburnan structure, such as vincamine and vincamon.

Furthermore, compounds of the general formulas IIa, IIb, Ile, Ild or II according to the invention are provided as active ingredient (s), expediently together with 1 or more customary pharmaceutical carriers and / or auxiliaries). As already mentioned, these compounds according to the invention have valuable pharmacological effects, in particular against circulatory diseases.

The l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino-no) -ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3- a] quinoli-zines of the general formulas IIa, IIb, Ile, Ild and II are also valuable intermediates for the preparation of other compounds with Eburnan skeleton, which also have valuable therapeutic properties, such as apovincamic esters of the formulas

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

656 128

14

fia) 5

(Ib)

(le)

and or

(Id) 35

or racemic trans- and / or cis-apovincamic acid reesters of the general formula

(I)

wherein

Ri and R2 are the same or different and stand for alkyl radicals with 1 to 6 carbon atoms.

The invention is illustrated by the following examples.

Example 1: 60

(-) -lß {[2 '- (methoxycarbonyl) -2' - (hydroxyimino j] ethyl} -la-ethyl-l, 2,3,4,6,7,12J2ba-octahydroindolo [2,3-aquinolizine and its hydrochloride

A) (-) - l ß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine -5-ium - (-) - dibenzoyl tartrate 65 and (+) - l a- [2 '- (methoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7-hexahydro-12H -indolo [2,3-a] quinolizin-5-ium- (-) -dibenzoyltar-tetr as well as the corresponding methanolates and perchlorates

100.0 g (0.2699 mol) of l- [2 '- (methoxycarbonyl) ethyl] -1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3 -a] Quinolizine-5-iumomethanolate was dissolved in 200.0 cm3 of dichloromethane at room temperature and a solution of 100.0 g (0.2673 mol) of dibenzoyl-1-tartaric acid monohydrate in 400 was added to the solution with stirring or shaking. 0 cm3 dichloromethane added. The mixture was

Stirred or shaken for 1 hour at room temperature and then the separated substance was filtered off, washed with dichloromethane and dried.

So 91.84 g [0.1322 mol] (98.0% of theory, based on the a-ethyl form) (-) -1 ß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1, 2,3,4,6,7-hexahydro-l 2H-indolo [2,3-a] quinolizine-5-ium - (-) - diben-coyl tartrate with a melting point of 139.5 to 140: C, a [ ajo 'value of -68.6 (c = 1, dimethylformamide) and a base content of 48.49% by weight (theoretically: 48.73% by weight).

After the base had been released, the corresponding methanolate (-) - lß [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7- hexahydro-12H-indolo [2,3-a] quinolizine-5-iumethanolate with a melting point of 151 to 152 C and an [aß value of -27.6 (c = 1, dimethylformamide) and (-) - 1 ß - [2 '(Methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7-hexa-hydro-12H-indolo [2,3-a] quinolizine-5-iumperchlorate with a melting point from 178 to 180; C and an [aJo value of - 23.5 C (c = 1, dimethylformamide) obtained.

The antipodes (+) - la- [2 '- (meth-oxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2, 3-a] quinolizine-5-ium - (+) - dibenzoyl tartrate and, after the base has been released, the corresponding methanolate and the corresponding hydrochloride are prepared in a known manner.

B) (-) - 1 ß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12b a-octahydroindolo [2,3-a] quinolizine - (-) - dibenzoyl tartrate

34.7 g (0.05 mol) of the (-) - lß- [2 '- (methoxycarbonyl) ethyl] -la-ethyl-1,2,3,4 obtained as described in section A) above, 6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-ium - (-) - dibenzoyl tartrate in 70 cm3 dimethylformamide in the presence of 0.25 g 10% palladium on bone carbon for 2.5 hours 40 C hydrogenated under atmospheric pressure. The catalyst was then filtered off and mixed with a total of 10 cm3 of dimethylformamide

2 servings washed. 200 cm 3 of 5% strength aqueous methanol were added dropwise to the filtrate with vigorous stirring or shaking, whereupon (-) - lß- [2 '- (methoxycarbonyl) ethyl] -la-ethyl-1,2,3,4,6, 7,12,12ba-octahydroindolo [2,3-a] quinolizine - (-) - dibenzoyl tartrate. This was washed with a total of 10 cm3 of cold methyl alcohol in 2 portions and dried.

Thus 26 g (75% of theory) (-) - lß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12ba- octahydroindolo [2,3-a] chi-nolizin - (-) - dibenzoyl tartrate with a melting point of 150 to 152: C and an [aß value of -120.1: (c = 2, dimethylformamide).

C) (-) - 1 ß - [[2 '- (methoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -la a-ethyl-1,2,3,4,6,7,12,12ba- octahydroindolo [2,3-a] quinolizine and its hydrochloride a) 34 g (0.1 mol) of (-) -lß- [2 '- (methoxycarbonyl) ethyl] obtained as described in section B) above were obtained. -l a-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine - (-) - dibenzoyl tartrate in a known manner released (-) - lß- [2 ' - (Methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12ba-octahydroin-dolo] 2,3-a] quinolizine 20 cm3 absolute toluene, a 55 to 60 % toluene solution of 30 cm3 of tert-butyl nitrite and then 17 g (0.15 mol) of potassium tert-butoxide were added. It was stirred or shaken at 25 to 30 ° C. for 20 minutes and then 150 cm 3 of absolute methanol were added to the mixture and the mixture was stirred or shaken at 40 ° C. for 3 hours. The reaction mixture was then cooled to 20 ° C. and acidified to a pH of 1 with concentrated aqueous hydrochloric acid, and 50 cm 3 of water were then added to the mixture

15

656 128

water was added and the mixture was stirred or shaken at + 5 ° C. for 2 hours. The precipitated substance was filtered off, freed of potassium chloride by washing with water and dried.

So 32.5 g (80% of theory) (-) - lß - {[2 '- (Methoxycar-bonyl) -2' - (hydroxyimino)] - ethyl} -1 a-ethyl-1,2,3 , 4,6,7,12,12ba-octa-hydroindolo [2,3-a] quinolizine hydrochloride with a melting point of 265 to 272 ° C (with decomposition) and an [aJc value of - 57 ° (c = 1, Dimethylformamide) obtained.

The free base was prepared from this in such a way that the former was suspended in 80 cm 3 of methanol and a mixture of 25 cm 3 of a 25% strength aqueous ammonium hydroxide solution and 40 cm 3 of water was added dropwise to the suspension with stirring or shaking. After stirring or shaking for 1 hour, the mixture was cooled to 10 ° C and filtered, and the filter residue was washed with water and dried. Thus 24 to 25 g of (-) - lß - {[2 '- (methoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -1 a-ethyl-1,2,3,4,6,7 , 12,12ba-octahy-droindolo [2,3-a] quinolizine with a melting point of 208 to 210 ° C and a [oJo value of - 62 ° (c = 1, dimethylformamide).

b) The above procedure a) was repeated with the difference that 15 g of sodium tert-butoxide were used instead of the potassium tert-butoxide.

Thus 24 g (60% of theory) (-) - lß - {[2 '- (methoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -1 a-ethyl-1,2,3,4 , 6,7,12,12ba-octahy-droindolo [2,3-a] quinolizine with the data given in procedure a).

c) The above procedure b) was repeated with the difference that 7 cm 3 of absolute dimethylformamide were added to the mixture.

So 32.5 g (80% of theory) (-) - lß - {[2 '- (Methoxycar-bonyl) -2' - (hydroxyimino)] - ethyl} -l ß-ethyl-1,2,3 , 4,6,7,12,12ba-octa-hydroindolo [2,3-a] quinolizine with the data given in procedure a).

Example 2:

(- j-lß- {[2'- (À thoxycarbonyl) -2'- (hydroxyimino)] ethyl} -la-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2 , 3-a] quinolizine and its hydrochloride

Sections A) and B) of Example 1 were repeated. Thereafter, with 34 g (0.1 mol) of (-) - lß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12ba thus obtained -octahydroin-dolo [2,3-a] quinolizine, the procedure of Example 1, Section C) a) was carried out with the difference that 150 cm 3 of absolute ethanol were used in place of the methanol.

Thus 25 g (60% of theory) (-) - lß - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -1 a-ethyl-1,2,3,4 , 6,7,12,12ba-octahy-droindolo [2,3-a] quinolizine hydrochloride with a melting point of 257 to 260 ° C and an [a] î> ° value of - 55 ° (c = 1, dimethylformamide) receive.

The base was released in aqueous ethanol using a 25% aqueous ammonium hydroxide solution as described in Example 1, Section C) a).

Thus 21 g of (-) - lß - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino-no)] - ethyl} -1 a-ethyl-1,2,3,4,6,7,12 , 12ba-octahydroindolo [2,3-a] chi-nolizin with a melting point of 172 to 173: C and a [ya] ™ value of - 118 = (c = 1, chloroform).

Example 3:

(+) -la - {[2 '- (À thoxycarbonyl) -2'-! hydroxyimino)] ethyl I-1ß-ethyl-1, 2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine and its hydrochloride

A) (+) - 1 a- [2 '- (methoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine -5-ium (+) - dibenzoyl tartrate and (-) -lß- [2 '- (methoxycarbonyl) ethyl] -la-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2 , 3-a] quinolizin-5-ium- (+) -dibenzoyltar-tetr as well as the corresponding methanolates and perchlorates

100.0 g (0.2699 mol) of l- [2 '- (methoxycarbonyl) ethyl] -1-ethyl-1,2,3,4,6,7-hexahydro-l 2H-indolo [2, 3-a] quinolizine-5-iumomethanolate at room temperature in 200.0 cm3 of dichloromethane and a solution of 100.0 g (0.2673 mol) of dibenzoyl-d-tartaric acid monohydrate was added to the solution with stirring or shaking 400 cm3 of dichloromethane added. After stirring or shaking at room temperature for 1 hour, the mixture was filtered and the filter residue was washed with dichloromethane and dried.

io So 91.7 g [0.1320 mol] (97.8% of theory, based on the β-ethyl form) (+) - la- [2 '- (methoxycarbonyl) ethyl] -lß-ethyl-1 , 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-ium - (+) - diben-coyltartrate with a melting point of 139 to 140 ° C, an [a] j> value of + 68.8 ° (c = 1, dimethylformamide) and a base content 15 of 48.5% by weight (theoretically: 48.73% by weight).

After the base had been released, the corresponding methanolate (+) - la- [2 '- (methoxycarbonyl) ethyl] -l β-ethyl-1,2,3,4,6,7- hexahydro-12H-indolo [2,3-a] quinoli-zin-5-iumethanolate with a melting point of 150 to 152 ° C 20 and an [aJ ^ value of + 27.8 ° (c = 1, dimethylformamide) and the corresponding perchlorate (+) - la- [2 '- (methoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine -5-iumperchlorate with a melting point of 178.5 to 180 ° C and an [a] 5 ° value of + 24 ° (c = 1, dimethylformamide). 25 From the mother liquor, the antipodes (-) - lß- [2 '- (meth-oxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2 , 3-a] quinolizine-5-ium - (-) - dibenzoyl tartrate and after the release of the base the corresponding methanolate and the corresponding perchlorate are obtained in a known manner.

30 B) (+) - la- [2 '- (methoxycarbonyl) ethyl] -lß-ethyl-

1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine The procedure of Example 1, Section B) was repeated with the difference that 34.7 g (0 , 05 mol) of the (+) - 1 a- [2 '- (methoxycarbonyl) ethyl] -1 β-ethyl-1,2,3,4,6,7-hexahydro- obtained as described in section A) above 12H-indolo [2,3-a] quinolizin-5-ium - (+) - dibenzoyltartra-tes were used.

So 25.5 g (73.5% of theory) (+) - la- [2 '- (Methoxycar-40 bonyl) ethyl] -l ß-ethyl-1,2,3,4,6,7 , 12,12bß-octahydroindolo [2,3-a] quinolizine with a melting point of 150 to 151 ° C and an [ajo value of + 119.8 ° (c = 2, dimethylformamide).

C) (+) - la - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -lß-ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [ 2,3-a] quinolizm and 45 its hydrochloride

The procedure of Example 1, Section C) a) was repeated with the difference that 34 g (0.1 mol) of (4-) -1 a- [2 '- (methoxycarbonyl) obtained as described in Section B) above were obtained as the starting substance ) -ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12b ß-50 octahydroindolo [2,3-a] quinolizine and 150 cm3 absolute ethanol were used as alcohol.

So 25.2 g (60% of theory) (+) - la - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -1 ß-ethyl-1,2,3 , 4,6,7,12,12bß-octahy-droindolo [2,3-a] quinolizine hydrochloride with a melting point 55 of 258 to 260 ° C and an [a] o value of + 55 ° (c = 1, dimethylformamide ) receive.

The base was released in aqueous ethanol using a 25% aqueous ammonium hydroxide solution according to the procedure of Example 1, Section C) a). 60 21.3 g of (+) -la - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimi-no)] - ethyl] -1 ß-ethyl-1,2,3,4,6, 7,12,12bß-octahydroindolo [2,3-a] chi-nolizin with a melting point of 171 to 172 ° C and an [a] j> ° value of + 118 ° (c = 1, chloroform).

65 Example 4:

(+) -lß- [[[2 '- (methoxycarbonyl) -2' - (hydroxyimino) J-ethyl} -la-ethyl-l, 2,3,4,6,7,12,12bß-octahydroindolo [2 , 3-a] quinolizine and its hydrochloride

656 128

16

A) (+) - 1 ß- [2 '- (methoxycarbonyl) ethyl] -l a-ethyl-1,2,3,4,6,7,12,12b ß-octahydroindolo [2,3-a] quinolizine a) 4.39 g (0.01 mol) of (-) - lß- [2 '- (methoxycarbonyl) ethyl] -la-ethyl-1,2, prepared as described in Example 1, section A), 3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate at 60 ° C in 100 cm3 of methyl alcohol and the suspension was stirred at this temperature for 1 hour with stirring or shaking Several portions of 1.2 g of sodium borohydride were added and the mixture was stirred or shaken for a further hour. 70 cm 3 of methyl alcohol were then distilled off from the reaction mixture under reduced pressure, the residue was filtered at 0 ° C. and the filter residue was first covered with cold methyl alcohol and then washed with distilled water until the neutral reaction was achieved and dried.

So 1.7 g (50% of theory) (+) - lß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7,12, Obtained 12bß-octahydroindolo [2,3-a] chi-nolizin with a melting point of 108 to 109e C and an [a] ™ value of -5- 69.7 (c = 1, chloroform).

b) 34 g (0.1 mol) were obtained according to the procedure in section a) above, but using racemic l- [2 '- (methoxycarbonyl) ethyl] -l-ethyl-l, 2,3 , 4,6,7-hexahy-dro-12H-indolo [2,3-a] quinolizine-5-iumperchlorate as the starting substance obtained racemic trans-l- [2 '- (methoxycarbonyl) -ethyl] -l-ethyl-l , 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine at 55 = C in 400 cm3 of methyl alcohol and then a solution of

15 g (0.1 mol) of D-tartaric acid in 40 cm3 of methyl alcohol were added. The homogeneous solution was cooled to 15 ° C., the crystals which separated out, which consisted of (+) - lß- [2 '- (methoxycarbonyl) ethyl] -la-ethyl-1,2,3,4,6,7,12, Passed 12bß-octahydroindolo [2,3-a] quinolizin-5-ium-D-tartrate, were filtered off and washed with a total of 50 cm3 of cold methanol in 2 portions and dried.

Thus 24.1 g (98.3% of theory) (+) - lß- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7, Obtained 12.12bß-octahydroindolo [2,3-a] quinolizin-5-ium-D-tartrate with a melting point of 213 to 215 C and an [a] b ° value of 44.8 (c = 1, dimethylformamide) .

The corresponding base was released from this as follows. It was dissolved in 200 cm 3 of water, the pH of the solution was adjusted to 9 with an aqueous ammonium hydroxide solution, then extracted with a total of 120 cm 3 of dichloromethane in 3 portions, the separated organic phase was dried and filtered, and the filtrate became an oil evaporated and the evaporation residue was heated to boiling with 30 cm3 of methyl alcohol.

Thus, 15.5 g (91.5% of theory) (+) - 1β- [2 '- (methoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6 as the excreted product , 7, 12, 12b-octahydroindolo [2,3-a] quinolizine with a melting point of 108.5 to 109: C and a [rajo value of +70.1: (c = 1, chloroform).

B) (+) - 1 ß- [2 '- (methoxycarbonyl) ethyl-la-ethyl-1,2,3,4,6,7,12,12b ß-octahydroindolo [2,3-a] quinolizine (+) - lß- [2 '- (carboxy-ethyl) -1 a-ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quino-lizine

A mixture of 6.8 g (0.02 mol) of (+) - lß- [2 '- (methoxycarbonyl) ethyl] -1, 2,3,4 obtained as described in section A) above was obtained. 6,7,12,12bß-octahydroindolo [2,3-a] quinolizine, 80 cm3 methanol, 4 cm3 water and 2 g solid sodium hydroxide were heated to boiling under reflux for 1 hour, after which 50 cm3 was distilled off from the mixture under reduced pressure, 80 cm 3 of water were added to the distillation residue and the solution was acidified with an aqueous solution of citric acid at 60 ° C. to a pH of 6.5. The precipitated product was filtered off at 20 C and washed with a total of 50 cm3 of distilled water in 2 portions and dried.

So 6.34 g (99% of theory) (+) -lß- [2 '- (carboxy) ethyl] -l a-ethyl-1,2,3,4,6,7,12,12bß- octahydroindolo [2,3-a] quinolizine with a melting point of 144: C (with decomposition) and an [aJo 'value of +52.4' (c = 1, ethanol).

This was esterified in the usual way with methanol to (+) -lß- [2 '- (methoxycarbonyl) ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine .

C) (+) - 1ß- {[2 '- (Methoxycarbonyl) -2' - (hydroxyimino) ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [2 , 3-a] quinoIizin and its hydrochloride

Example 1, section C) a) was repeated with the difference that 34 g (0.1 mol) obtained as starting substance (+) - lß- [34] (0.1 mol) as described in section A) or in sections A) and B) above. 2 '- (Methoxycarbonyl) ethyl] -la-ethyl-l, 2,3,4,6,7, 12,12bß-octahydroindolo [2,3-a] quinolizine were used.

Thus 25 g (61.5% of theory) (+) - lß {[2 '- (methoxycarbonyl) -2' - (hydroxyimino)] ethyl} -1 a-ethyl-1,2,3,4 , 6,7,12,12bß-octahy-droindolo [2,3-a] quinolizine hydrochloride with a melting point of 214 to 215: C and an [a] o value of +46: (c = 1, dimethylformamide).

The base was released from this as follows. It was suspended in 50 cm 3 of water, 100 cm 3 of chloroform were added to the suspension, and the mixture was then made alkaline to pH 9 with stirring or shaking with a 25% strength aqueous ammonium hydroxide solution. The chloroform phase was separated and the aqueous phase was extracted with 20 cm 3 of chloroform. The combined organic phases were dried over anhydrous solid sodium sulfate and filtered, the filtrate was evaporated under vacuum and the residue was recrystallized from 30 cm 3 of dichloroethane.

So 19.2 g (+) -lß - [[2 '- (methoxycarbonyl) - (hydroxyimino-no)] - ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12bß- octahydroindolo [2,3-a] chi-nolizin with a melting point of 166 to 168: C and an [a] b 'value of +53.2 (c = 1, dimethylformamide).

Example 5:

i - _l-la-) [2'- <methoxycarbonyl> -2'- <hydroxyimino i] -ethylJ-lß-ethyl-1,2,3,4,6,7.12.12hH-Pctahyiiruindolo [2.3-a] quinoli : in and its hydrochloride

A) (-) -la- [2 '- (Methoxycarbonyl j-ethyl] -l ß-ethyl-1,2,3.4.6.7.12, 12ba-octahydroindoio [2,3-a] quinolizine a) Example 4, section A ) a> was repeated with the difference that 4.39 g (0.01 mol) of (+) -la- [2 '- (methoxycarbonyl) ethyl] obtained as described in Example 3, Section A) was obtained as the starting substance. -l ß-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinoli-zin-5-iumperchlorate were used.

So 1.73 g (51% of theory) (-) -1 a- [2 '- (methoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12a -octahydroindolo [2,3-a] quino-lizin with a melting point of 108 to 109 ° C. and an [a] o value of -68.9 (c = 1, chloroform).

b) The methanolic mother liquor from the cleavage obtained according to Example 4, Section A), procedure b), first paragraph, was concentrated to a volume of 100 cm3, diluted with 200 cm3 of water and after treatment with an aqueous ammonium hydroxide solution (pH = 9) extracted with a total of 120 cm3 dichloromethane in 3 portions. The separated organic phase was dried and filtered and the filtrate was evaporated to an oil and heated to boiling with 30 cm 3 of methanol.

15.1 g (89% of theory) (-) - 1 a - [2 '- (methoxycarbonyl) ethyl] -l ß-ethyl-1,2,3,4,6,7, 12.12b a-octahydroindolo [2,3-a] quinolizine with a melting point of 109 C and an [aß 'value of -69.4: (c = 1, chloroform).

B) (-) -1 a- [2 '- (methoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12b a-octahydroindolo [2,3-a] quinolizine over (-) -la- [2 '- (carboxy) ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quino- lizin p

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Example 4, section B) was repeated with the difference that 6.8 g (0.02 mol) of (-) - la- [2 '- (methoxycarbonyl) ethyl] obtained as described in section A) above were obtained as the starting substance. lß-ethyl-l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine was used.

So 6.3 g (98.5% of theory) (-) - la- [2 '- (carboxy) ethyl] -ß-ethyl-l, 2,3,4,6,7,12,12ba -octahydroindolo [2,3-a] quinolizine with a melting point of 144 ° C (with decomposition) and an [a] o value of -48.6 ° (c = 1, ethanol) and from this (-) - la - [2 '- (Methoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12ba-octahydroin-dolo [2,3-a] quinolizine obtained.

C) (-) - la - {[2 '- (methoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -lß-ethyl-l, 2,3,4,6,7,12,12ba-octahydroindolo [ 2,3-a] quinolizine and its hydrochloride

Example 1, section C) a) was repeated with the difference that 34 g (0.1 mol) obtained as the starting substance as described in section A) above or in sections A) and B) above (-) - la- [ 2 '- (Methoxycarbonyl) ethyl] -lß-ethyl-l, 2,3,4,6, 7,12,12ba-octahydroindolo [2,3-a] quinolizine were used.

Thus 24.3 g (60% of theory) (-) - la - {[2 '- (Methoxycar-bonyl) -2' - (hydroxyimino)] - ethyl} -lß-ethyl-l, 2,3, 4,6,7,12,12ba-octa-hydroindolo [2,3-a] quinolizine hydrochloride with a melting point of 214 to 215 ° C and an [ajo value of -46 ° (c = 1, dimethylformamide).

From this, the base was released according to the procedure of Example 4, Section C) releasing the base.

Thus 19 g (-) - la - {[2 '- (methoxycarbonyl) -2' - (hydroxyimino-no)] - ethyl} -1 ß-ethyl-1,2,3,4,6,7,12 , 12ba-octahydroindolo [2,3-a] chi-nolizin with a melting point of 166 to 168 ° C and an [a] r> value of -54 ° (c = 1, dimethylformamide).

Example 6:

A) (-) - 1 a- [2 '- (ethoxycarbonyl) ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12b a-octahydroindolo [2,3-a] quinolizine a) Example 5, section B) was repeated with the difference that the esterification was carried out with ethanol instead of with the methanol.

There was thus obtained (-) - la- [2 '- (ethoxycarbonyl) ethyl] -lß-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine.

b) Example 5, section A) or sections A) and B) was repeated with the difference that the starting substance according to the procedure of Example 3, section A), but from l- [2 '- (ethoxycarbonyl) - ethyl] -1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo- [2,3-a] quinolizine-5-iumethanolate obtained (+) - 1 a- [2 ' - (Ethoxycarbonyl) ethyl] 1-ß-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-iumperchlorate was used.

There was thus obtained (-) - la- [2 '- (ethoxycarbonyl) ethyl] -lß-ethyl-l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolizine.

B) (-) - la - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -lß-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [ 2,3-a] quinolizine hydrochloride

The procedure was as described in Example 1, Section C) a), but 35.4 g (0.1 mol) of (-) - la- [2 '- (ethoxycarbonyl) obtained as described in Section A) above was used as the starting substance ) -ethyl] -1 ß-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-

656 128

a] quinolizine and 150 cm3 absolute ethanol were used as alcohol.

So 23 g (55% of theory) (-) - l - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -1 ß-ethyl-1,2,3,4,6 , 7,12,12ba-octahydroin-dolo [2,3-a] quinolizine hydrochloride with a melting point of 247 to 249 ° C and an [ajo value of -44 ° (c = 1, dimethylformamide).

Example 7:

A) (+) - 1 ß- [2 '- (ethoxycarbonyl) ethyl] -1 a-ethyl-1,2,3,4,6,7,12,12b

ß-Octahydroindolo [2,3-a] quinolizine a) Example 4, section B) was repeated with the difference that the esterification was carried out with ethanol instead of with the methanol.

There was thus obtained (+) - lß- [2 '- (ethoxycarbonyl) ethyl] -la-ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine.

b) Example 4, section A) or sections A) and B) was repeated with the difference that the starting substance according to the procedure of Example 1, section A), but from l- [2 '- (ethoxycarbonyl) - ethyl] -l-ethyl-l, 2,3,4,6,7-hexahydro-12H-indolo- [2,3-a] quinolizine-5-iumethanolate (-) - lß- [2'- (Ethoxycarbonyl) ethyl] la ethyl 1, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-iumperchlorate was used.

There was thus obtained (+) - lß- [2 '- (ethoxycarbonyl) ethyl] -la-ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine.

B) (+) - l ß - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -l a-

ethyl-1,2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine hy-

hydrochloride

The procedure was as described in Example 1, Section C) a), but 35.4 g (0.1 mol) of (+) - lß- [2 '- (ethoxycar-bonyI) obtained as starting substance as described in Section A) above ) -ethyl] -la-ethyl-l, 2,3,4,6,7,12,12bß-octahydroindolo [2,3-a] quinolizine and 150 cm3 absolute ethanol were used as alcohol.

23.2 g of (+) - lß - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimi-no)] - ethyl} -1 a-ethyl-1,2,3,4,6,7 , 12, 12bß-octahydroindolo [2,3-a] quinolizine hydrochloride with a melting point of 248 to 249 ° C. and an [aJo value of +45: (c = 1, dimethylformamide).

Example 8:

Racemic trans-1 - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino) J-

ethyl} -l-ethyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizinhy-

hydrochloride

The procedure was as described in Example 1, Section C) a), but 35.4 g (0.1 mol) of racemic trans-1 - [2 '- (ethoxycarbonyl) ethyl] -l-ethyl-1 as starting substance, 2,3,4,6,7,12,12b-octa-hydroindolo [2,3-a] chmolizin, which is as described in Example 4, Section A) or Sections A) and B), but with racemic l- [ 2 '- (Ethoxycarbonyl) ethyl] -l-ethyl-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-iumperchlorate as a starting substance, and 150 cm3 of absolute ethanol were used as alcohol.

Thus 25.1 g (60% of theory) of racemic trans-l - {[2 '- (ethoxycarbonyl) -2' - (hydroxyimino)] - ethyl} -l-ethyl-l, 2,3,4,6 , 7,12, 12b-octahydroindolo [2,3-a] quinolizine hydrochloride with a melting point of 226 to 228 ° C (with decomposition) and an [a] D value of ± 0 (c = 1, dimethylformamide).

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Claims (10)

656128 1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas and / or (Hld) 3 to optically active trans-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas 40 (Via) (Ha) (IIb) O K - OH respectively so (VIb) or to optically active cis-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general Formulas (VIc) 65 (Ile) (Hd) 21-OH n. - o - c - c * II H2 E2 in which R [and R2 are identical or different and represent alkyl radicals having 1 to 6 carbon atoms, 656 128 1 to 6 carbon atoms are as well as acid addition salts of these compounds, characterized in that racemic l- [2 '- (alkoxycarbo- nyl) ethyl] -1-alkyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinole- zin-5-ium derivatives of the general formula 60 0 N - OH wherein R! and R2 are the same or different and represent alkyl radicals having 1 to 6 carbon atoms, 65 as well as their acid addition salts. 1, characterized in that the alkyl radicals for which R 1 and R stand are those with 1 to 4, in particular 1 or 2, carbon atoms. 1. Optically active trans- and / or eis-1- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b -octahydroindolo- [2,3-a] quinolizines of the general formulas 2 -0-C - C - C II II ' OH OK and or (iid) O — C - C - O X - OH or racemic trans and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b -octahy- (IVc) 35 droindolo [2,3-a] quinolizines of the general formula and / or (II) OVd) ' hydrogenated, and the compounds obtained are treated directly with tert-alkyl nitrites having 4-8 C atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates and the compounds obtained are converted, if appropriate, into acid addition salts. 2. l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine according to claim (V) 2nd PATENT CLAIMS 3rd 656128 wherein R3 corresponds to the radical R2 or is different therefrom and means alkyl having 1-6 carbon atoms and X is an acid residue or an alkanolate residue with 1 to 6 carbon atoms, with optically active dibenzoyl tartaric acid to optically active l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium derivatives of the general formulas and / or (Va) (Illb) subjects them to optically active trans-l- [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines 15 of the general formulas and / or (Vb) (Via) and or 30th splits and this either (a) with alkali metal hydrides to optically active trans-1- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo- [2,3- a] quinolizines of the general formulas 35 (VIb) (IVa) 40 and or esterified, wherein R4 corresponds to or is different from the radical R3 and means alkyl with 1-6 carbon atoms, and this with tert-alkyl nitrites with 4 to 8 carbon atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates, whereby compounds of Receives formulas IIa and IIb, or that one (b) the compounds of the formulas Va and / or Vb listed above catalytically to give optically active cis-1- [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6, 7,12,12b-octahydroindolo [2,3-a] quinolines of the general formulas (IVb) reduced, this an alkaline hydrolysis to optically active trans-1 - [2 '- (carboxy) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo- [2,3 -a] quinolizines of the general formulas 60 (purple) 65 (IVc) (IVd) 656 128 3. Process for the preparation of optically active trans-5 and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-1,2,3,4,6, 7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas (IIa) 2f - OK (IIb) 0 H - 01t 0 N - OH respectively 30th (Ile) 0 S - OH and or (Ild) O K - OH or racemic trans- and / or cis-l- [2 '- (alkoxycarbosonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7,12, 12b-octahy-droindolo [2,3-a] quinolizines of the general formula (IIa) (IIb) (Hc) (Ild) (II) wherein R] and R2 are the same or different and for alkyl radicals 4. Process for the production of racemic trans and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-l, 2,3,4,6,7, 12,12b-octahydroindolo [2,3-a] quinolizines of the general formula 50 (III) converted this to racemic trans- and / or cis-l- [2 '- (alkoxy-carbonyI) -ethyl] -l-alkyl-I, 2,3,4,6,7, I2, I2b-octahydroindoIo [2 , 3-a] quinolizines of the general formula 60 (II) 0 H - OH (VI) wherein R4 represents an alkyl radical having 1 to 6 carbon atoms which corresponds to the radical R3 or is different from it, 4th hydrogenated, this by alkaline hydrolysis in optically active cis-l- [2 '- (carboxy) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3- a] Quinolizines of the general formulas in which Rj and R2 are identical or different and stand for alkyl radicals having 1 to 6 carbon atoms, and acid addition salts of these compounds, characterized in that racemic 1 - [2 '- (alkoxycarbonyl) ethyl] -1 -alkyl-1,2,3,4,6,7-hexahydro-l 2H-indolo [2,3-a] quinolizine-5-ium derivatives of the formula (never) and or (V) (Illd) 20 converted by esterification into optically active cis-l- [2 '- (alk-oxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3 -a] quinolizines of the general formulas in which R3 corresponds to the radical R2 or is different therefrom and represents an alkyl radical having 1 to 6 carbon atoms and X denotes an acid residue or an alkanolate residue with 1 to 6 carbon atoms, to racemic trans- and / or cis-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7 , 12,12b-octahydroindolo- [2,3-a] quinolizines of the general formula (IV) (VIc) and or 35 reduced, wherein racemic compounds of formula V with alkali hydrides to racemic trans compounds of formula IV and racemic compounds of formula V are catalytically reduced to racemic cis compounds of formula IV, the racemic trans and / or cis compounds of formula IV by alkaline hydrolysis in racemic trans- and or cis-l- [2 '- (carboxy) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3 -a] quinolizines of the general formula (VId) 45 transferred and finally treated with tert-alkyl nitrites with 4 to 8 carbon atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates, whereby compounds of the formulas Ile and Ild are obtained and compounds obtained are converted into acid addition salts if necessary. 5. Process for the preparation of optically active trans- and / or eis-1 - [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-l, 2,3,4,6,7 , 12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas and / or (IVb) or optically active cis-l- [2 '- (alkoxycarbonyl) ethyl] -l- (Ila) alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizine the general-15 my formulas r ^> and or (IVc) (IIb) 25 and / or respectively 30th (IVd) (Hey) 0 2f - OH and / or in what R3 corresponds to the radical R2 or is different therefrom and denotes alkyl having 1-6 carbon atoms, 40 an alkaline hydrolysis to optically active trans-l- [2 '- (carboxy) -ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3- a] quinoli-zinen of the general formulas (Ild) W - OH where Rj and R2 are identical or different and represent alkyl radicals having 1 to 6 carbon atoms, and acid addition salts of these compounds, 55 characterized in that optically active trans-1- [2 '- (alk-oxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3- a] quinolizines of the general formulas (purple) and or (IVa) (IHb) or to optically active cis-l- [2 '- (carboxy) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general Formulas 656 128 5 656 128 esters and treated with tert-alkyl nitrites having 4 to 8 carbon atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates and the compounds obtained, if appropriate, converted into acid addition salts. 6. Process for the preparation of optically active trans- and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-aIkyI-10 1,2,3,4,6, 7, 12, 12b-octahydroindolo [2,3-a] quinolizines of the general formulas (Hld) subjects these obtained compounds to optically active trans-I - [2 '- (alkoxycarbonyl) ethyl] -I-alkyl-1,2,3,4,6,7,12,12b-octahy-droindolo [2,3 -a] quinolizines of the general formulas (VI) (IIa) (IIb) and / or o H - OK or r ^ v (VIb) (Hey) - 0 - 0 - 0 - C * ' II E2 H2 OH OH and or 45 or optically active cis-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas (Ild) (VIc) O K - OH in which Rj and R2 are identical or different and denote alkyl having 1 to 6 carbon atoms, as well as acid addition salts of these compounds, characterized in that optically active trans-1- (2 '- (carboxy) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-ajinolizine der general formulas (VId) (purple) 6 and / or esterified, in which R4 represents an alkyl radical having 1 to 6 carbon atoms, which corresponds to or is different from the radical R3, and finally the compounds obtained with tert-alkyl nitrites with 4-8 C atoms in aromatic hydrocarbon ( IIIc) 5 solvents and then treated with tert-alkali metal alcoholates and the compounds obtained, if appropriate, converted into acid addition salts. 7 656 128 and / or and / or (IHb) (Yld) or optically active cis-l- [2 '- (carboxy) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas esterified, in which R4 is an alkyl radical having 1 to 6 carbon atoms, which corresponds to the radical R3 or is different therefrom, and finally the compounds obtained with tert-15 alkyl nitrites with 4-8 carbon atoms in aromatic hydrocarbon solvents and then with tert - Treated alkylimetal alcoholates and, if appropriate, obtained compounds converted into acid addition salts. (IIIc) 7- Process for the production of optically active trans and / or cis-20 1 - [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl- 8. Process for the preparation of optically active trans- and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -l-alkyl-l, 2,3,4,6,7 , 12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas 45 50 (Va) and or (Ha) M - OK (Vb) wherein R3 corresponds to or is different from the radical R2 and represents an alkyl group with 1-6 carbon atoms and X represents an acid residue or an alkanolate residue with 1-6 carbon atoms 65, either (a) with alkali metal hydrides to form optically active trans-1- [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo- [2,3- a] quinolizines of the general formulas 8th and acid addition salts of these compounds, characterized in that optically active trans-l- [2 '- (alk-oxycarbonyl) ethyl] -l-alkyl-l, 2,3,4,6,7,12,12b-octahydroindolo [2,3- ajchinolizine of the general formulas and / or (Via) (Hb) O K - OH respectively and / or (VIb) or optically active cis-l- [2 '- (alkoxycarbonyl) ethyl] -l-alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinolizines of the general formulas (Ile) O S - OK and or 30th (Ild) (VIc) O X - OH 35 in which Rj and R2 are identical or different and represent alkyl radicals having 1 to 6 carbon atoms, and acid addition salts of these compounds, characterized in that optically active l- [2 '- (alkoxycar-bonyl) ethyl] -l-alkyl-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] chino-40 lizin-5-ium derivatives of all my formulas (VId) wherein R4 stands for an alkyl radical having 1 to 6 carbon atoms, which corresponds to the radical R2 or is different therefrom, treated with tert-alkyl nitrites with 4-8 C atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcohols and obtained Compounds optionally converted into acid addition salts. 9. Medicament, characterized in that it contains at least one compound from the group of optically active trans- and / or cis-l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimi-no) ethyl] -1 - as active ingredient. alkyl-1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a] quinoli-zine of the general formulas o H - OH R, and R, are the same or different and represent alkyl radicals having 1 to 6 carbon atoms, or acid addition salts of these compounds. 9 656 128 r ^> (IVa) s (IIb) and or or r ^ N- (IVb) reduced, and the compounds obtained are treated directly with tert-alkyl nitrites with 4-8 C atoms in aromatic hydrocarbon solvents and then with tert-alkali metal alcoholates, and the compounds obtained are optionally converted into acid addition salts, or that (b) the compounds of the formulas Va and / or Vb listed above catalytically to give optically active cis-1- [2 '- (alkoxycarbonyl) ethyl] -1-alkyl-1,2,3,4,6, 7,12,12b-octahydroindolo [2,3-a] quinolines of the general formulas (Ile) 10. Medicament according to claim 9, characterized in that it is a l- [2 '- (alkoxycarbonyl) -2' - (hydroxyimino) ethyl] -1-alkyl-1,2,3,4,6,7 as active ingredient , 12, 12b-octahydroindolo- [2,3-a] quinolizine, in which R 1 and R 2 have 1 to 4, in particular 1 or 2, carbon atoms. (Ha) H - OK